Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.9.3.1 (cytochrome oxidase)
 8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Niemann-Pick type C1 (NPC1) disease is a rare neurovisceral disorder characterized by intracellular accumulation of unesterified cholesterol, sphingolipids, and other lipids in the lysosomal compartment. A deregulation of lysosomal calcium has been identified as one of the earliest steps of the degenerative process. Since adenosine A2A receptors (A2ARs) control lysosome trafficking and pH, which closely regulates lysosomal calcium, we hypothesized a role for these receptors in NPC1. The aim of this study was to evaluate the effects of the A2AR agonist CGS21680 on human control and NPC1 fibroblasts. We show that CGS21680 raises lysosomal calcium levels and rescues mitochondrial functionality (mitochondrial inner membrane potential and expression of the complex IV of the mitochondrial respiratory chain), which is compromised in NPC1 cells. These effects are prevented by the selective blockade of A2ARs by the antagonist ZM241385. The effects of A2AR activation on lysosomal calcium are not mediated by the cAMP/PKA pathway but they appear to involve the phosphorylation of ERK1/2. Finally, CGS21680 reduces cholesterol accumulation (Filipin III staining), which is the main criterion currently used for identification of a compound or pathway that would be beneficial for NPC disease, and such an effect is prevented by the Ca(2+) chelator BAPTA-AM. Our findings strongly support the hypothesis that A2AR agonists may represent a therapeutic option for NPC1 and provide insights on their mechanisms of action.
...
PMID:The stimulation of adenosine A2A receptors ameliorates the pathological phenotype of fibroblasts from Niemann-Pick type C patients. 2406 6

The ATPase Inhibitory Factor 1 (IF1) is the physiological inhibitor of the mitochondrial ATP synthase. Herein, we summarize the regulation of the expression and activity of IF1 as a main driver of the activity of oxidative phosphorylation (OXPHOS) in mammalian tissues. We emphasize that the expression of IF1, which is a mitochondrial protein with very short half-life, is tissue-specifically expressed and primarily controlled at posttranscriptional levels. Inhibition of the activity of IF1 as inhibitor of the ATP synthase under normal physiological conditions is exerted by phosphorylation of S39 by a cAMP-dependent PKA-like activity of mitochondria in response to different physiological cues. Conditional tissue-specific transgenic mice overexpressing IF1 in colon, or a mutant active version of IF1 (IF1-H49K) in liver or in neurons, revealed the inhibition of the ATP synthase and the reprograming of energy metabolism to an enhanced glycolysis. In the IF1-H49K models, the assembly/activity of complex IV and the superassembly of complex V are also affected. Moreover, the IF1-mediated inhibition of the ATP synthase generates a reactive oxygen species (mtROS) signal that switches on the expression of nuclear genes that facilitate adaptation to a restrained OXPHOS. In contrast to normal mice, metabolically preconditioned animals are partially protected from the action of cytotoxic agents by upgrading the activation of stress kinases and transcription factors involved in resolving metabolic adaptation, the antioxidant response, cell survival, and the immune response of the tissue microenvironment. Altogether, we stress a fundamental physiological function for the ATP synthase and its inhibitor in mitohormesis.
 ...
PMID:A Review of the Inhibition of the Mitochondrial ATP Synthase by IF1 in vivo: Reprogramming Energy Metabolism and Inducing Mitohormesis. 3028 62


<< Previous 1 2